HIF‐1α in cartilage homeostasis, apoptosis, and glycolysis in mice with steroid‐induced osteonecrosis of the femoral head

Abstract

With the prevalence of coronavirus disease 2019, the administration of glucocorticoids (GCs) has become more widespread. Treatment with high‐dose GCs leads to a variety of problems, of which steroid‐induced osteonecrosis of the femoral head (SONFH) is the most concerning. Since hypoxia‐inducible factor 1α (HIF‐1α) is a key factor in cartilage development and homeostasis, it may play an important role in the development of SONFH. In this study, SONFH models were established using methylprednisolone (MPS) in mouse and its proliferating chondrocytes to investigate the role of HIF‐1α in cartilage differentiation, extracellular matrix (ECM) homeostasis, apoptosis and glycolysis in SONFH mice. The results showed that MPS successfully induced SONFH in vivo and vitro, and MPS‐treated cartilage and chondrocytes demonstrated disturbed ECM homeostasis, significantly increased chondrocyte apoptosis rate and glycolysis level. However, compared with normal mice, not only the expression of genes related to collagens and glycolysis, but also chondrocyte apoptosis did not demonstrate significant differences in mice co‐treated with MPS and HIF‐1α inhibitor. And the effects observed in HIF‐1α activator‐treated chondrocytes were similar to those induced by MPS. And HIF‐1α degraded collagens in cartilage by upregulating its downstream target genes matrix metalloproteinases. The results of activator/inhibitor of endoplasmic reticulum stress (ERS) pathway revealed that the high apoptosis rate induced by MPS was related to the ERS pathway, which was also affected by HIF‐1α. Furthermore, HIF‐1α affected glucose metabolism in cartilage by increasing the expression of glycolysis‐related genes. In conclusion, HIF‐1α plays a vital role in the pathogenesis of SONFH by regulating ECM homeostasis, chondrocyte apoptosis, and glycolysis.